Opiate addiction is a major health problem, with close to a million users in the United States. The traditional treatments attempt to increase the addict's will power to withstand the craving for opiates but do not decrease the craving itself. For a large percentage of addicts this is not sufficient: eventually they, give in to the craving and resume using the drugs.
The most successful treatment currently used is methadone maintenance therapy. It reduces mortality (Gr onbladh et al., 1990) and social problems related to criminality (Ladewig, 1990). The relative success of this procedure is largely does to the fact that it does deal with the opiate craving. The craving is satisfied with a legally-prescribed opiate--methadone--and thus the patient has little motivation to obtain illegal opiates.
Unfortunately, methadone maintenance therapy has "a serious limitation . . . [because] clients have difficulty tapering off methadone" (Ladewig, 1990, p. 246). Clinicians, most addicts, and society in general would prefer that methadone maintenance were only a temporary phase for the patient, eventually replaced by a drug-free existence. This ideal, however, is seldom met, and for many addicts methadone maintenance appears to be a life-long program. There are other disadvantages to methadone maintenance therapy, including side-effects and illegal diversion of the methadone, but almost all of the disadvantages are caused by or increased by the lack of an effective method for terminating the therapy.
The present invention provides a safe and effective method for terminating methadone maintenance. After controlled withdrawal, the patient takes methadone while an opiate antagonists blocks positive reinforcement. As a result, the methadone-taking responses are extinguished and the craving for methadone is eliminated. An additional procedure is also provided to help guard against resumption of opiate use.
The present invention has the following significant advantages:
1. It is legally acceptable. Many years ago, A. Wikler among others speculated that heroin addiction might be treated with an extinction procedure involving opiate antagonists: "the narcotic antagonist-maintained patient, while still in the hospital . . . should be required to self-inject genuine, guaranteed pure heroin repeatedly" (Wikler, 1973, p. 615). Theoretically, the procedure almost certainly would be useful. Practically, however, it has never been used clinically. Probably a major reason why it has not been used is because it would be illegal. In the United States, heroin normally cannot legally be given to any patient. The practical difficulties and the feelings of most clinicians against allowing heroin self-administration in a treatment center have probably also help to keep the procedure from being used. PA1 2. It reduces craving and should be effective. Extinction requires that the opiate-seeking responses be made while reinforcement is blocked. The only way that opiate antagonists have previously been used in the treatment of opiate addiction is with a procedure designed to prevent all opiate use, "for maintenance of the drug-free state" (Jepsen. 1990, English abstract). For example, one clinical trial with 1005 addicts had the subjects being informed that because of the antagonist small doses of opiates would not produce pleasant effects, but large doses could be fatal (Renault, 1980). Although extinction is sometimes mentioned in the rationale for such studies, the actual procedure prevents extinction in all subjects who obey the instructions. Opiate antagonists alone do not reduce the craving for opiates nor does simply knowing that taking opiates will not produce euphoria. Most of the subjects in the Renault study dropped out, and there were no significant benefits. Other studies have shown that although the procedure is better than the traditional procedures in highly motivated subjects, it is not as effective as methadone maintenance therapy (Jepsen, 1990). As Frank H. Gawin stated recently (quoted by M. Holloway, 1991): "Just blocking the euphoria is not the panacea that some naive individuals think it is." PA1 3. It closely reproduces during extinction the stimulus situation to which opiate-taking had been learned. A form of extinction without antagonists, called "cue exposure", has subjects being presented with the external stimuli related to drug taking and/or making the preparatory responses for self-administration of a drug, but not actually taking the drug. (e.g., G. A. Marlatt, 1990; O'Brien et al., 1990). The physical controls to prevent drug taking, however, inevitably change the situation for the subject, thus reducing the effectiveness of extinction. These controls are not needed in the present invention because an opiate antagonist is used instead to prevent reinforcement. PA1 5. It includes a process referred to herein as "selective extinction". The probability that an opiate-seeking response will be emitted is not determined by the absolute strength of the response but rather by its strength relative to all competing responses. Some of the competing responses (e.g., eating highly palatable foods) are also reinforced by the opioidergic system. Keeping an addict continually on an opiate antagonist would extinguish these competing responses, thus reducing the relative effect of weakening the opiate-seeking response. Nevertheless, a major goal in the past and today (Holloway, 1991) has been preparations such as naltrexone implants that would keep patients continually under the influence of an antagonists for weeks or months after a single administration. Advocates of extinction also failed to see the problem: e.g., Wikler (1973) wrote that the patient should be maintained continually on the narcotic-antagonist for a year.
Permission has been obtained for experimental tests of Wikler's idea. Mello et al. (1981) found that naltrexone effectively suppressed heroin self-administration in an operant situation. A second study (see O'Brien et al., 1988) also found some evidence for suppression but was limited by dysphoria. The third study (Meyer, 1988) allowed patients to work for and obtain heroin in a treatment ward. Because of the setting, the procedure should not be expected to extinguish the previously learned opiate-taking responses and thus would not be very effective as a treatment, but it should extinguish opiate-taking in the ward. Half of the subjects did stop working for heroin almost completely after the first dose and showed a progressive decrease in craving. Although others continued to work for it, they also showed a progressive decrease in craving after the third day. However, because the patients did not show an "extinction burst", i.e., an initial increase in responding for heroin when the antagonist was first introduced, the author concluded that the data "did not appear to be consistent with models of operant extinction in the animal literature" (p. 164) and explained the results instead in terms of discriminative learning. The progressive decreases in craving, however, are not consistent with discriminative learning. Furthermore, an extinction burst is not always found in animal studies and especially not in animal studies with drug taking and opiate antagonists: no extinction bursts were found in rat studies with alcohol drinking (Sinclair, U.S. Pat. No. 4,882,335, 1989; Sinclair, 1990) which otherwise were always consistent with extinction, nor was one found by Davis and Smith (1974) in a study they felt showed extinction of opiate-seeking with naloxone in rats.
The legally-acceptable and practical method disclosed in the present invention, in which methadone is self-administered after an antagonist is given, has not previously been proposed. Furthermore, it should work even better than Wikler's method. Heroin is taken in a wide variety of situations. The methadone-taking response, however, needs to be extinguished primarily, or with many patients exclusively, in a single situation--at the treatment center where it has previously been given--and, from a practical viewpoint, this is an ideal situation for conducting extinction sessions.
Extinction, however, does reduce craving. In the Renault study, 17 patients disobeyed instructions and, as required for extinction, took opiates while on naltrexone. These patients showed significant improvement and reduction in reported craving.
The antagonist may produce another advantage over cue exposure. Opiate-seeking responses probably are reinforced not only from the opiates self-administered but also partly from the thrill and stimulation involved in the procurement and taking of the drug. The possibility that this additional reinforcement might also be mediated by the opioidergic system is suggested by findings that the reinforcement from other forms of stimulation--e.g., from pleasant tastes, physical exertion, and sexually-related stimuli--is controlled by the system. (In experiments, e.g., saccharin drinking was apparently extinguished with naloxone.) Stimuli previously associated with opiates may gain the ability to activate the opioidergic system and thereby also produce additional reinforcement. The opiate antagonist in the present invention would block this additional reinforcement, but cue exposure would not.
4. It is medically safe. The only previous proposal for a practical method for extinguishing a drug-taking response with opiate antagonists is earlier patent (Sinclair, U.S. Pat. No. 4,882,335, 1989). This was for the treatment of alcoholism rather than opiate addiction and thus differs in many ways from the present invention. Of most importance, the alcoholism treatment must begin while the subjects are still physiologically dependent in order to avoid the giving alcohol to withdrawn alcoholics forbidden by ethical guidelines. This procedure, however, would be medically very dangerous for opiate addicts because the antagonist would cause precipitous withdrawal.
The present invention is not dependent upon the eventual development of sustained-release preparations; indeed they would be counterproductive. The selective extinction procedure intersperses extinction sessions when the major activity is opiate-seeking behavior with periods when the patient is free of antagonist and able to make all responses except for opiate-seeking. Any competing responses that happen to be weakened during the extinction sessions are strengthened when they are emitted and reinforced during the intervening periods. Thus it changes extinction with antagonists from being a crude method with broad behavioral effects into a precise tool for removing only a specific response.
Selective extinction also has the advantage that it should minimize adverse side-effects from the antagonists. For example, problems from the liver toxicity of naltrexone develop only after prolonged continual administration (Morgen and Kosten, 1990). Further, the dysphoria reported by some patients maintained on naltrexone, which may contribute to high drop-out rates, may be caused by the antagonist continually blocking many sources of pleasure, and should be reduced if in selective extinction since they are free to enjoy other opioidergically-reinforced activities other than opiate-seeking.